| Summary: | 碩士 === 國防醫學院 === 微生物及免疫學研究所 === 92 === Autoimmune destruction of islets in the pancreas leads to the development of insulin-dependent diabetes mellitus (IDDM). The panel of pro-inflammatory cytokines including interferon-γ (INF-γ), interleukin-β (IL-β), tumor necrosis α (TNF-α); free radicals such as nitric oxide (NO); and Fas-mediated apoptosis contribute to this destructive pathogenesis. Heme oxygenase-1 (HO-1), which catalyzes the degradation of heme to carbon monoxide (CO), iron and biliverdin, has recently been shown to exert strong cytoprotection against inflammatory cytokine-, free radical- or FasL-induced apoptosis. In this study, we further investigate the therapeutic potential and mechanism of HO-1 in autoimmune diabetes. First approach in my thesis is to systemically increase HO-1 expression in NOD mice by CoPP (Co3+ protophrin IX chloride) induction and to see whether overexpression of HO-1 can mediate protective in type 1 diabetes. Second, we generated the insulin promoter-driving HO-1 transgenic NOD and to evaluate their protective potential and mechanisms. Furthermore, we will transplant diabetic NOD mice with islets tranduced by lenti-mHO-1 virus and then access their potential immunoprotective effect.
Our preliminary data show that HO-1 upregulation by CoPP injection can prevent NOD mice from diabetes. Transgenic mice with human insulin promoter/mHO-1 gene were generated to expectedly overexpression HO-1 on beta cells of prancreatic islets. Eight transgenic founders containing the transgene were identified by southern blot analysis. These founders were successfully bred to establish transgenic NOD lines. We will monitor diabetic frequency and investigate the potential protective mechanism in HIP-mHO-1 transgenic mice.
Finally, we have established lentivirus and islet transplantation system in our laboratory. We will transplant infected-islet cells to diabetic NOD mice and observe whether the can rescue diabetes.
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